This invention relates to novel rifamycin derivatives having antimicrobial activity, compositions containing the compounds, and methods for treatment and prevention of microbial infections. The compounds of the current invention are potent antibacterial agents active against certain drug-resistant, and particularly rifamycin-resistant pathogens.
Rifamycins are natural products with potent antimicrobial activity. Examples of the naturally-occurring rifamycins are rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV and rifamycin Y (Brufani et al., 1974). The therapeutic applications of the naturally-occurring rifamycins are limited due to their poor oral bioavailability, weak activity against Gram-negative pathogens and low distribution into the infected tissues. Significant efforts have been made toward to identifying semi-synthetic rifamycin derivatives to address the deficiencies. As a result, many semi-synthetic rifamycin derivatives with improved spectrums and pharmacological profiles have been identified. Among the semi-synthetic compounds, rifampin, rifabutin and rifapetine have been developed into therapeutic agents and are widely used for the treatment of tuberculosis and other microbial infections (Farr, Rifamycins).
One of the major problems associated with the rifamycin class of antimicrobial agents is the rapid development of microbial resistance. Compounds of the current invention are designed to address the rifamycin resistance problem by covalently attaching another functional group to the C-25 position of rifamycin scaffold that provides an additional binding interaction with RNA polymerase or interacts to an additional enzyme target.
Reference is made to U.S. Pat. No. 4,188,321 that describes a series of C-25 desacetyl derivatives and Wehrli, Zimmerman et al., 1987, that discloses a series of C-25 rifamycin derivatives modified through an ester linkage. The compounds of the current invention are rifamycin derivatives having stable C-25 carbamate functionality, which are novel.
Reference is made to Kump and Bickel, 1973, which describes preparation of a propionate and pivalate esters at C-25. Reference is made to U.S. Pat. No. 5,786,350 that discloses a series of C-36 derivatives of rifamycins, including derivatives formed by linking the C-3 carboxy group of a fluoroquinolone to the C-36 position of rifamycins through a chemically and metabolically liable ester group. Compounds of the current invention link an antibiotic to the C-25 position of rifamycins through a chemically and metabolically stable carbamate linker.
Reference is also made to International Patent Application Publication No. WO 03/045319 A2 which discloses rifamycin derivatives formed by linking rifamycin and a therapeutic drug and the use of these derivatives as vehicles for delivering the therapeutic drug. However, the aforementioned reference failed to demonstrate by specific examples that any drug is introduced to the C-25 position of a rifamycin molecule. Derivatives in which the C-25 acetate is replaced by a carbamate linkage are not described and no examples for the preparation of such examples are known.